The Evolution of Endocrinology

Plenary Lecture at the 12th International Congress of Endocrinology, Lisbon, Portugal, 31 August 2004

Jean D. Wilson

Disclosures

Clin Endocrinol. 2005;62(4):389-396. 

In This Article

Adolescence

Whatever the weakness of the rejuvenation claims (and it took many years to disprove them), many scientists recognized the explanatory potential of the concept of chemical messengers and were stimulated to investigate extracts of other organs. Within a short time proof was obtained for the existence of multiple chemical messengers, and a dynamic discipline was born. Early milestones in the field are summarized in Table 1 . In 1891, only two years after Brown-Sequard's lecture, Murray administered thyroid extract to a woman with myxoedema. In 1894 Oliver and Schäfer described epinephrine in extracts of the adrenal medulla. In 1903 Bayliss and Starling discovered secretin, and Starling chose the term hormone to describe all chemical messengers. In succession, Bouin and Ancel deduced the role of the Leydig cells in development of the male phenotype; MacCallum and Voetlin discovered the link between the parathyroid glands and calcium metabolism; Farmi and von den Velden treated diabetes insipidus with posterior pituitary extracts; Evans and Long described growth hormone; and in 1922 came the discovery of insulin by Banting and Best. By this time it was clear that hormones influence almost every function in the body. More importantly, at a time when few drugs of any type were effective, epinephrine was in use as a pressor substance, and organ extracts were available for three major disorders hypothyroidism, diabetes insipidus and diabetes mellitus.

This brief summary does not do justice to the rapid, almost explosive growth of the new discipline. In 1910, Artur Biedl, Professor of General and Experimental Pathology at the German University in Prague, published a textbook of endocrinology[5] that was promptly translated into English. The book listed more than 8500 references, only about 1% of which had been published prior to 1889. This averages to more than 400 papers a year during the first 20 years of the field. The second edition in 1916 had almost 10 000 references.

Endocrine societies (under a variety of names) were formed in many countries, and dedicated journals were established, beginning in 1917 with the publication of Endocrinology in the United States, followed by endocrine journals in Italy ( Endocrinologia e Pathologica Constituzionals ), France ( Revue Francaise d'Endocrinologie ) and Germany ( Endokrinologie ). According to Medvei,[6] the publication rate in the field increased to about 1500 papers a year by the end of the 1920s.

A major impetus for this growth came from the fact that by the end of the nineteenth century many disorders were known to be associated with pathology in specific organs. For example, diabetes mellitus was linked to the pancreas, adrenal insufficiency and pheochromocytoma to the adrenals, hyperthyroidism and myxoedema to the thyroid, and acromegaly and gigantism to the pituitary. In addition, the effects of surgical castration of men and women were understood in considerable detail.

The possibility that such disorders might be due to over- or underproduction of chemical mediators had been widely discussed. For example, shortly after the description of adrenal insufficiency by Thomas Addison in 1855, Brown-Séquard showed that surgical removal of the adrenal is lethal to dogs but was unable to keep adrenalectomized dogs alive by administering adrenal extracts. Subsequent investigators were also unsuccessful in prolonging life in Addison's disease with adrenal extracts.[7] Consequently, it is not surprising that Brown-Séquard's lecture stimulated a variety of collaborations between basic and clinical scientists.

As formulated by Doisy,[8] hormone development involved a series of stages:

  1. Identification of the tissue that produces a hormone

  2. Development of bioassay methods to identify the hormone

  3. Preparation of active extracts that can be purified, using the relevant bioassay

  4. Isolation, identification of structure, and synthesis of the hormone.

Clinicians were adept in identifying candidate organs and hormones, development of bioassays was made possible by advances in physiology and pharmacology, and purification, structural analysis and synthesis required organic chemists.

The most dramatic example of early hormone development is that of epinephrine.[6] In 1894 George Oliver, a physician in Harrogate, had the idea that patients with low blood pressure might benefit from extracts of the adrenal. Therefore, he prepared a glycerin extract of beef adrenal medulla obtained from the local butcher, injected the extract into his son, and observed contraction of the boy's radial artery. [Sir Henry Dale[9] commented that the boy deserved a memorial.] Oliver went to London and persuaded the somewhat sceptical pharmacologist Edward Schäfer to inject the extract into a dog that had an intra-arterial monitor in place. This famous experiment is illustrated in Fig. 1 - a kymograph tracing of the rise in arterial blood pressure in the dog following the administration of Oliver's extract. In 1897 Abel and Crawford at the Johns Hopkins Hospital used the Oliver/Schäfer bioassay to purify the active principle as a monobenzoyl derivative of epinephrine that was not very active physiologically.

The effect of extracts of the suprarenal capsule in the dog: (a) pressure in the ventricle; (b) pressure in the atrium; (c) blood pressure; (d) injection interval. From Oliver and Schäfer, Journal of Physiology, 1895, republished by Schäfer (1916).[51]

The therapeutic and financial potential of hormones had been apparent from the first, and it was inevitable that pharmaceutical companies would become involved in hormone development. In 1901 support from the Parke-Davis company allowed the Japanese-American Jokicki Takamine and an American, T. B. Aldrich, to purify the native hormone independently and establish its structure. To complete the story, the German chemist Friedrich Stolz synthesized epinephrine in 1904.

The importance of the bioassay in this process cannot be overemphasized. Such assays varied in simplicity and sensitivity from measurement of blood sugar response for insulin and the chick comb assay for testosterone to tedious and inefficient systems such as prolongation of life in the adrenalectomized dog by cortisone or assaying the regression of mullerian ducts in organ culture for antimullerian hormone. Some hormones were purified using bioassay systems that were not related to the main action of the hormone in mammals. For example, vasopressin was characterized as the pressor substance of the posterior pituitary rather than for its antidiuretic properties, and prolactin was purified using the pigeon crop assay.

By the mid-1920s endocrinology had completed its adolescence. It was an international undertaking that was stimulated by clinical problems; it involved collaborations between clinical and basic scientists; the research was financed in large part by the pharmaceutical industry; and it had undergone a remarkable growth to become a major branch of medicine and of biomedical science.

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